Loss of bladder control as a result of neurological disease or injury such as spinal cord injury (SCI) has devastating effects. SCI results in loss of voluntary control of bladder evacuation, bladder hyper-reflexia, and bladder sphincter dysynergia. These factors often lead to ureteric reflux and obstruction, infection of the kidneys, long-term renal damage, episodes of autonomic dysreflexia with dangerous rises in blood pressure, incontinence which contributes to skin breakdown, as well as frequent urinary tract infections. Loss of bladder control also has profound social impact and leads to decreased quality of life, as well as large direct medical costs from procedures, supplies, and medication. The long-term goal of this research is to develop a neural prosthesis to restore bladder function (continence and micturition) in persons with neurological disorders, particularly spinal cord injury. We are pursuing an innovative approach using electrical stimulation of afferent (sensory) fibers in the pudendal nerve (and its branches) that engage spinal reflexes that either inhibit the bladder to maintain continence or activate the bladder to produce micturition. This novel approach differs substantially from prior approaches using electrical stimulation of the spinal roots in that it does not require a spinal laminectomy, does not require irreversible surgical transection of the sacral sensory nerve roots, and stimulates the afferent rather than the efferent side of the system. During the first funding period we developed and evaluated a closed-loop control system to improve continence in both animals and in persons with spinal cord injury, we discovered and quantified the properties of reflexes that activated the bladder in response to pudendal afferent stimulation, we determined the surgical access to the pudendal n. and that the nerve is amenable to cuff implantation, and we designed a flat interface nerve electrode for selective stimulation of the human pudendal nerve. The overall objective of the present proposal is to increase the efficiency of bladder emptying achieved by electrical stimulation of pudendal afferents. In the previous period we discovered and characterized two reflexes that when activated by electrical stimulation of pudendal afferents excite the bladder, inhibit the sphincter, and produce micturition. However, the voiding that was achieved was limited, and in persons with chronic SCI, activation of pudendal afferents produced small amplitude or transient contractions of the bladder. Therefore, we will develop and evaluate several novel approaches to enhance bladder emptying induced by pudendal afferent stimulation through complementary experiments in an animal model and in persons with spinal cord injury. Successful completion of this project will advance the development of an effective neural prosthetic system for restoration of bladder function.